Preliminary Results Of A Cancer Research Uk Phase I Trial Combining The Dinitrobenzamide Prodrug Cb1954 (Tretazicar) And The Nqo2 Substrate Ep-0152r (Caricotamide)

2505 Background: CB1954 (CB) is a dinitrobenzamide prodrug that is converted in the presence of the enzyme NQO2 and co-substrate EP-0152R (EP) into a potent cytotoxic bifunctional alkylating agent. Methods: Patients (pts) with histologically confirmed advanced solid tumours and WHO Performance Status 0 - 2 were treated with CB and EP. CB was administered IV over 15 minutes midway through a 4 hour IV infusion of EP. Objectives were to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the combination, evaluate pharmacokinetics (PK) and pharmacodynamic (PD) effects and describe antitumour activity. PD effects were assessed in lymphocytes and tumour biopsies by the Single Cell Gel Electrophoresis (Comet) assay. Early PK data indicated that 200 mg/m2 EP maximally activated NQO2. Subsequent patients were treated at this dose whilst dose escalating CB in cohorts of 3–6 patients. Results: 29 pts (median age 57 yrs; 15 Male/14 Female) were treated in 5 cohorts (escalating doses of CB: 12, 16, 20, 26.6, 35 mg/m2). DLTs were seen at 26.6 mg/m2 (1 pt, grade 3 transaminitis), and in 2 pts at 35 mg/m2 (1 pt grade 3 transaminitis and 1 pt grade 3 diarrhoea). Other drug-related toxicities at these dose levels included grade 1 - 3 nausea and vomiting, and grade 2 anorexia, dehydration and abdominal pain. Exposure to CB increased in a supra-proportional manner with increasing dose. CB elimination was very rapid when co-administered with EP, with mean clearance being up to 970-fold higher than when administered alone, resulting in a plasma t1/2 of 2 - 5 minutes. The consequent decrease in CB area under curve was consistent with EP activating NQO2 conversion of CB. PD analysis showed evidence of DNA interstrand cross-linking in lymphocytes, and in 1 melanoma pt where tumour was obtained. 1 pt with ocular melanoma had evidence of stable disease for over 4 months. Conclusions: The combination of CB and EP was well tolerated with MTD defined as CB 26.6 mg/m2 with EP 200 mg/m2. This cohort is being expanded to define PD effects in tumour. No significant financial relationships to disclose.